Experimental background 4. Geometrical and Energetic Bases of reaction mechanisms

1. Experimental background 4. Geometrical and Energetic Bases of reaction mechanisms 5. Typical reaction mechanisms - free radical halogenations of methane and other saturated hydrocarbons - conditions for competing reactions such as substitution and elimination - spatial arrangement of MO and reaction stereochemistry - hard and soft acids and bases - thermodynamic and kinetic control of competing mechanism - potential energy surface

2. Geometrical and Energetic Bases of reaction mechanisms Geom. & Energ. Bases Competing reactions: two types of second order reactions can be distinguished: SN2 E2 Solomons 269 Bruckner I-220 March’s 1300

3. -78.03171814 Geom. & Energ. Bases -76.01074643 E2 -458.91415079 -538.13151999 SN2 -75.3265988 -154.07574482 EtCl + OH major product EtOH minor product (1%) CH2=CH2 314.7 kcal/mol E2 293,8 kcal/mol memo: at RHF/6-31G(d) gas phase the major product is EtOH (SN2) ~21 kcal/mol! However the reaction will not take place in the gas phase ~300 kcal/mol? SN2 0 RHF/6-31G(d)

4. Geom. & Energ. Bases vSN2 = kSN2[R-Cl][OH-] vE2 = kE2[R-Cl][OH-] the goal is to demonstrate that for parallel or competing mechanisms, the product ratio in the reaction mixture, at any time during the reaction, is equal to the rate constant ratio The energetics of the reactions, may be measured by reaction kinetics determines which one of two mechanism dominates. Both reactions follow second order kinetics:

5. Geom. & Energ. Bases Geom. & Energ. Bases Experimentally measured concentrations as function of the reaction time the rates of consumption of A: integrated rate equ. differential rate equ. [A] = [A]0 exp(-kt) individual rates of product formation: with the initial conditions: [X]0 = [Y]0 = 0

6. Experimental background 4. Geometrical and Energetic Bases of reaction mechanisms 5. Typical reaction mechanisms - free radical halogenations of methane and other saturated hydrocarbons - conditions for competing reactions such as substitution and elimination - spatial arrangement of MO and reaction stereochemistry - hard and soft acids and bases - thermodynamic and kinetic control of competing mechanism - potential energy surface

7. General equationsfor the various mechanisms Typical reaction mech. Typical reaction mech. Nucleophil Substitution on saturated carbon atoms: example: Nucleophil Substitution on aromatic carbon atoms: where X electron withdrawing group

8. Electrophilic Substitution on saturated carbon atom: Typical reaction mech. example: Electrophilic Substitution on aromatic carbon atom :

9. Radical Substitution on saturated carbon atom: Typical reaction mech. Typical reaction mech. alkyl hypochlorite forming “stable” alkoxy radical example: memo: Ra := initiator radical R := radical R-Cl := the looked-for alkyl halogenid Radical Substitution on aromatic carbon atom : Sykes 57 Sykes 61

10. Nucleophil addition on unsaturated carbon atom: Typical reaction mech. Typical reaction mech. Typical reaction mech. example: Electrophil addition on unsaturated carbon atom: Solomons 734 Sykes 75

11. Radical addition on unsaturated carbon atom: Typical reaction mech. example: Sykes 88

12. Base induced (nucleophilic) elimination on saturated carbon atom: Typical reaction mech. Typical reaction mech. Bimolecular (E2) Unimolecular:E1cB Unimolecular:E1

13. Acid induced (electrophilic) elimination on saturated carbon atom: Typical reaction mech. Radical elimination on saturated carbon atom: Sykes 156

14. Free radical halogenations of methane and other saturated hydrocarbons Typical reaction mech. at B3LYP/6-311++G(d,p) no vibrational corr. 157 kcal/mol -207 kcal/mol -49 kcal/mol Homolytic bond dissociation energies How to determine whether a reaction is endo- and exothermic? Determine the corresponding bond dissociation energies (BDE). HH + ClCl2 HCl BDE(kcal/mol): 104 + 58 +(-103 x 2) = 162+(- 206) H of reaction = -206 - ( -162 ) = -44 kcal/mol

15. Homolytic and heterolytic bond dissociation energies Typical reaction mech. Note that: the heterolytic (ionic) dissociation requires (103 + 230.4 = 333.4 kcal/mol) is more than three times that of the homolytic (free-radical) dissociation (103 kcal/mol). Furthermoer: This holds for organic molecules also: Conclusion: direct contrast with the experience there must be an explanation! Answer: the effect of the solvent

16. Answer: Both cations and anions are strongly solvated by polar solvents such as H2O. Therefore 1. ionic reactions are energetically more favourable in polar solvent Typical reaction mech. Typical reaction mech. 2.free-radical reactions are energetically more preferred, in the gas phase or in a non-polar solvents where the above stabilization is not possible, Typical textbook values of selected BDE values in kcal/mol.

17. Typical reaction mech. If the free-radical is generated thermally, then BDE is the energy requirement If the free-radical is generated photochemically, then more than the BDE is needed Free-radical reactions: halogenation of hydrocardons In ionic reactions electrons moved in pairs In free-radical reactions, only one electron moves in a given step In stable organic molecules electrons are always paired. Thus, a free-radical needs to be generated to initiate a radical mechanism.

18. Typical reaction mech. energy requirement is the BDE Cl2+58 kcal/mol. bond- breaking bond-making overall reaction Hreaction Ereaction = BDEproduct - [-BDEreactant] -104 - (-103) =1 an example: the chlorination of methane

19. BDEH-CH3= +104 kcal/mol BDEH-CH3= +104 kcal/mol BDEH-CH3 = +104 kcal/mol BDEH-CH3= +104 kcal/mol BDEH-F = +136 kcal/mol BDEH-Cl = +103 kcal/mol BDEH-Br = +87.5 kcal/mol BDEH-I = +71 kcal/mol DH = -32 kcal/mol DH = 1 kcal/mol DH = 16.5 kcal/mol DH = 33 kcal/mol Hreaction = BDECl2 - [-BDECl-CH3] -58 - (-83.5) = -25.2 Hreaction = BDEC-CH3 - [-BDEH-Cl] -104 - (-103) = 1 BDEF–F2 F = +38 kcal/mol BDECl–Cl2 Cl = +58 kcal/mol BDEBr–Br2 Br= +46 kcal/mol BDEI–I2 I = +36 kcal/mol BDEF-CH3 = +108 kcal/mol BDECl-CH3 = +83.5 kcal/mol BDEBr-CH3 = +70kcal/mol BDEI-CH3 = +56 kcal/mol DH = -70 kcal/mol DH = -25.2 kcal/mol DH = -24kcal/mol DH = -20 kcal/mol

20. DH = -32 kcal/mol + DH = 1 kcal/mol + DH = 16.5 kcal/mol + DH = 33 kcal/mol + DH = -70 kcal/mol DH = -25.2 kcal/mol DH = -24kcal/mol DH = -20 kcal/mol = -102.0 kcal/mol F = -24.2 kcal/mol C l = -7.5 kcal/mol Br = +13.0 kcal/mol I Typical reaction mech. Energy profile for the methane halogenation chain propagation steps (H3CH + X  H3C + HX and XX + CH3  X + XCH3) for X = F, Cl, Br and I. Reaction with iodine is very endothermic (+13 kcal/mol) It doesn’t occur! Reaction with bromine is slightly exothermic (-7.5 kcal/mol) Sluggish, selective reagent. Reaction with chlorine is rather exothermic (-24.2 kcal/mol) Ferocious, not very selective reagent. Reaction with fluorine is very exothermic (-102 kcal/mol) Explosion!

21. Typical reaction mech. Chlorine bites off H atom from almost any CH bond Bromine can bite off only H atoms from sec. and tert. C atoms Example for selectivity: chlorination is not really selective (-24.2 kcal/mol) bromination is more selective (-7.5 kcal/mol) six H atoms attached to primary carbon atom two H atoms attached to secondary carbon atom Calculation of Hreaction for [9.10] using the thermochemical equation [9.7]

22. Typical reaction mech. Example for stereochemistry if a chiral centre is formed during halogenation then the reaction will yield a racemic mixture if the molecule have an optically active compound, then the resulting compound will be diastereomeric.

23. Reactivity and Selectivity Typical reaction mech. Typical reaction mech. Cl. is more reactive than Br. For H attached to primer C atom Ea(Cl)1 < Ea(Br)1 For H attached to sounder C atom Ea(Cl)2 < Ea(Br)2 Br. is more selective than Cl.

24. Typical reaction mech. polarity stabilizes carbocations (and haloids) thus give chance to E1 rate const. ratio product ratio Conditions for competing reactions such as substitution and elimination less polar more polar highly polar SN2 and E2 as well as SN1 and E1 mechanisms may occur in competition The structure of the substrate can discriminate between SN2 or the SN1 The polarity of the solvent can discriminate between SN2 or the SN1

25. Typical reaction mech. The relative magnitude of the rate constants is determined by the basicity of the nucleophile used product ratio rate const. ratio Strong Bronsted bases is more effective in removing a proton from the intermediate carbocation than weak ones. for strong bases for weak bases An examples EtO- stronger base than EtOH conclusion E1 > SN1

26. Examples Typical reaction mech. E1 < SN1 weaker bases The two second-order rate constants kSN1 and kE2 reflect the difference in basicity of the nucleophile used E1 > SN1 stronger bases

27. Spatial arrangement of MO and reaction stereochemistry Typical reaction mech. the HOMO of the nucleophile The Frontier Molecular Orbital (FMO), (HOMO/LUMO) approach Spatial arrangements of molecular orbitals are crucial for the stereochemistry of a reaction: e.g. SN2. backside attack on the C - Cl bond is due to the orientation of the LUMO of the R-Cl along the C - Cl axis, pointing away from the carbon Solomons 235 & movie the HOMO of the substrate breaks up during the reaction when a new bond is formed the LUMO of the substrate interact SN2

28. Spatial arrangements of molecular orbitals are crucial for the stereochemistry of a reaction: e.g. E2. Typical reaction mech. Solomons 267, 288& movie

29. Spatial arrangements of molecular orbitals are crucial for the stereochemistry of a reaction: e.g. SN1 andE1. Typical reaction mech. Typical reaction mech. In SN1 the simple Lewis acid-base reaction, the collapse of the carbocation and hydroxide ion follows: The first step for the SN1 and E1 is common. It is a reverse Lewis acid-base reaction In E1, the carbocation behaves as a Bronsted acid and a proton is transferred from carbon to the base such as HO:(-) the carbocation is a -protonated carbon-carbon double bond:

30. The HOMO/LUMO involvement is a general principle of organic reactions. e.g. the addition reaction to a carbon-oxygen double bond (carbonyl compound): Typical reaction mech. The acid, A(+), attaches the HOMO and the base, :B(-), attaches the LUMO of the carbonyl compound. The orbital level diagram of H2C = O RHF/6-31G(d)

31. Typical reaction mech. Conservation of orbital symmetry (Fukui, Woodward and Hoffmann) is used to predict whether a reaction is allowed or forbidden. Overlaps between the HOMO of the reactant and the LUMO of the reagent is as follows: the positive lobe of overlaps with an other positive lobe and a negative only with an other negative lobe Further examples for FMO Diels-Alder reaction March’s 1068 Electrocycling rearrangement March’s 1428 Ring closure of dienes March’s 1429 Sigmatropic rearrangement March’s 1438

32. hard and soft acids and bases Typical reaction mech. Bronsted acidity: the proton donating ability in aqueous solution. (The pKa of an acid is related to the pH value of the aqueous solution) proton is transferred Bronsted base Bronsted acid Problem: the same type of simplicity is not present for defining Lewis acidity and basicity. electron pair is transferred Etymology: the “dative bond” of the Lewis comp. was donated by the base RHF/6-31G(d) Solomons 97,

33. the strengths of Lewis acids depend on the structure (polarizability) of the bases (acceptor) employed. Typical reaction mech. BX3 AlX3  FeX3  GaX3  SbX5  SnX4  AsX5  ZnX2  HgX2 Some characteristics of Lewis acids and bases [i] The softness of bases increases from left to the right according to rows and going dawn along the columns of the periodic table CH3-NH2- OH- F- orI- Br- Cl- F- softerharder orsofterharder

34. Selected hard and soft Lewis acids and bases Typical reaction mech. F- is a stronger base with respect to H+ I- is a stronger base with respect to Ag+ H+ is a stronger acid with respect to RNH2 Ag+ is a stronger acid with respect to phosphines (R3P) Examples: Ruff, Csizmadia 361

35. The principle of similarity: hard acids react favorably with hard bases and soft acids react favorably with soft bases. Typical reaction mech. Lewis complex to be formed is more stable if both the acid and base components are of the same hardness hard acids have a high-energy LUMO soft acids have a low-energy LUMO DE(HOMO-LUMO) is relatively large DE(HOMO-LUMO) is relatively small hard bases have a low-energy HOMO soft bases have a higher-energy HOMO stable but weaker bond of ionic nature e.g. H+ andF- →HF strong covalent bond is formed e.g. Br+ and CH3- →CH3Br The interaction in terms of frontier orbitals: mismatches: “hard and soft” e.g. H+ and I- →HI low stability complexes are formed

36. Nucleophiles and electrophiles Typical reaction mech. Lewis base as well as nucleophilic reagent Lewis acid as well as electrophilic reagent thermodynamic property kinetic property proton hard electroeophile bromine soft electroeophile Example 1: alkene soft nucleophile because of the principle of similarity for the above reactions: neutral or negatively charged compound containing lone electron pairs electron pair accepting molecules base strength measured by the protonation equilibrium, nucleophilicity by the rate of nucleophilic reaction.

37. proton hard electroeophile Typical reaction mech. because of the principle of similarity for the above reactions: nucleophiles with soft electrophiles: HS-CN- Br- Cl- OH- F- faster reaction slower reaction same nucleophiles with hard electrophiles: OH- > CN- > HS- > F- > Cl- > Br- > I- bromine soft electroeophile Example 2: Br2 hard nucleophile

38. Conclusion: soft nucleophiles + soft electrophiles orbital-controlled reaction orbital-controlled reaction driving force: HOMO-LUMO hard nucleophiles + hard electrophiles driving force: attraction of opposite charges charge-controlled reaction charge-controlled reaction Example: SN2 reaction: rate-determining step is te HOMO LUMO overlap SN1 reaction: rate-determining step the formation of the carbocation Application: fluoride ion is a hard nucleophile, thus, prepare fluoro compounds via SN1 reaction, enhance the reaction by choosing a good leaving group such as tosylate

39. Nucleophilicity and solvation Typical reaction mech. Large sized, soft nucleophiles, with a small negative charge density e.g. I-, SCN- form hydrogen bonds in protic solvents very weakly involved in hydrogen bonding extensive solvation their reactivity is enhanced their reactivity is decreased. Example: if theelectrophile is methyl iodide, then the order of nucleophilicity is as follows: in protic solvents I- > SCN-CN- > N3- Br- > Cl- > AcO- in dipolar aprotic solvents CN-AcO- Cl- Br- N3- > I- > SCN- Small sized, hard bases with a large negative charge density e.g. F-, Cl-, RO-

40. Electron supply and demand Typical reaction mech. The electronic effects of substituents: electron withdrawing groups (EWG) make a molecule less basic or more acidic electron donating groups (EDG) make a molecule more basic or less acidic. The effect of substituents on the FMO energies of Lewis acids and bases and their effect on the subsequent Lewis complex stability.

41. Thermodynamic and kinetic control of competing mechanism Typical reaction mech. Typical reaction mech. TS product [Y] [Y] [X] [X] Example: which of the isomers will be formed during a ER and anEN? more EDG higher stability less EDG lower stability Z Question: what will be the major product ? transition state stability and product stability predetermine X: a clear situation transition state stability indicate Y but product stability predetermine X: a bias situation Zaitsev rule Hoffman rule

42. Typical reaction mech. The size of the nucleophile (base) plays a dominant role in determining whether the Zaitsev or the Hofmann product is formed:

43. Potential Energy Surface (PES) representation • of chemical reaction Typical reaction mech. 3translational coordinates and 3rotational coordinates of a general n-atomic molecule leave (3n – 6) internal coordinates.